RU2023110768A - PHARMACEUTICAL COMPOSITIONS OF ANTIBODY TO HER2 DRUG CONJUGATE - Google Patents

Claims (29)

1. An aqueous liquid pharmaceutical composition of an antibody-drug conjugate, wherein the composition includes an antibody-drug conjugate, a non-reducing sugar, an amino acid and a solubilizer, the non-reducing sugar is selected from mannitol, sucrose, trehalose, and combinations thereof, the amino acid is selected from histidine, alanine, arginine, glycine, glutamic acid, the hydrochloride of the above amino acids, and combinations thereof, and the solubilizer is selected from glycerol, Tween 80, and combinations thereof. 2. Aqueous liquid pharmaceutical composition according to claim 1, where the concentration of mannitol is 100-300 mmol/l, preferably 190-300 mmol/l, more preferably 200-260 mmol/l and most preferably 240-260 mmol/l; the sucrose concentration is 0-100 mmol/l, preferably 40-100 mmol/l, more preferably 60-100 mmol/l and most preferably 40-60 mmol/l. 3. An aqueous liquid pharmaceutical composition according to claim 1 or 2, wherein the histidine is histidine hydrochloride at a concentration of 0-100 mmol/l, preferably 5-50 mmol/l, more preferably 5-20 mmol/l and most preferably 10 mmol/l l; arginine is arginine hydrochloride at a concentration of 0-160 mmol/l, preferably 20-100 mmol/l, more preferably 30-90 mmol/l and most preferably 35 mmol/l. 4. Aqueous liquid pharmaceutical composition according to any one of paragraphs.1-3, where the content of glycerol is 0-1%, preferably 0.2-0.5% (w/v); the mass percentage of Tween 80 is 0-0.02% (w/v). 5. An aqueous liquid pharmaceutical composition according to any one of claims 1 to 4, wherein the antibody of the antibody-drug conjugate is an anti-HER2 monoclonal antibody; and the drug is MMAE, MMAF, DM1, DM4 or a derivative thereof. 6. An aqueous liquid pharmaceutical composition according to claim 5, wherein the antibody-drug conjugate is an anti-HER2-vc-MMAE monoclonal antibody, wherein the anti-HER2 monoclonal antibody is linked to the MMAE via a vc linker, wherein the structure of the linker and the MMAE after their connection is as follows :

. 7. An aqueous liquid pharmaceutical composition according to claim 5 or 6, wherein the anti-HER2 monoclonal antibody comprises a heavy chain and a light chain, (i) the heavy chain includes CDR regions 1-3 having amino acid sequences as shown in SEQ ID NOs: 1, 2 and 3, respectively; and/or (ii) the light chain includes CDR regions 1-3 having amino acid sequences as shown in SEQ ID NOs: 4, 5 and 6, respectively; And the monoclonal antibody is preferably a chimeric antibody or a humanized antibody. 8. An aqueous liquid pharmaceutical composition according to any one of claims 1 to 7, wherein the concentration of anti-HER2-vc-MMAE monoclonal antibody is 5-30 mg/ml. 9. An aqueous liquid pharmaceutical composition according to claim 8, wherein the non-reducing sugar is 240-260 mmol/L mannitol and/or 40-60 mmol/L sucrose, the amino acid is 8-12 mmol/L histidine hydrochloride, and the solubilizer is 0-0.02% (w/v) Tween 80. 10. The aqueous liquid pharmaceutical composition of claim 9, wherein the non-reducing sugar is approximately 260 mmol/L mannitol and approximately 40 mmol/L sucrose, the amino acid is approximately 10 mmol/L histidine hydrochloride, and the concentration of the antibody-drug conjugate is approximately 10 mg/ml and the solubilizer is 0.02% (w/v) Tween 80. 11. The aqueous liquid pharmaceutical composition of claim 10, wherein the non-reducing sugar is approximately 240 mmol/L mannitol and approximately 60 mmol/L sucrose, the amino acid is approximately 10 mmol/L histidine hydrochloride, and the concentration of the antibody drug conjugate is approximately 10 mg. /ml, and the solubilizer is approximately 0.02% (w/v) Tween 80. 12. An aqueous liquid pharmaceutical composition according to any one of claims 1-11, wherein the composition has a pH of 4.5-7, preferably 5.6-6.8, more preferably 5.6-6.5, 5.6-6, 4, 5.6-6.3, 6.1-6.4 or 6.1-6.3. 13. A lyophilized pharmaceutical composition of an antibody-drug conjugate, wherein the lyophilized pharmaceutical composition is obtained by lyophilization of an aqueous liquid pharmaceutical composition according to any one of claims 1 to 12. 14. The lyophilized pharmaceutical composition of claim 13, wherein the aqueous liquid pharmaceutical composition comprises about 260 mmol/L mannitol, about 40 mmol/L sucrose, about 10 mmol/L histidine hydrochloride, about 0.02% (w/v) Tween 80 and about 10 mg/ml anti-HER2-vc-MMAE monoclonal antibody, and the aqueous liquid pharmaceutical composition has a pH of 5.6-6.8. 15. The lyophilized pharmaceutical composition of claim 13, wherein the aqueous liquid pharmaceutical composition comprises about 240 mmol/L mannitol, about 60 mmol/L sucrose, about 10 mmol/L histidine hydrochloride, about 0.02% Tween 80, and about 10 mg/L. ml of monoclonal antibody against HER2-vc-MMAE, and the aqueous liquid pharmaceutical composition has a pH of 5.6-6.8. 16. The lyophilized pharmaceutical composition of claim 13 wherein the non-reducing sugars in the aqueous liquid pharmaceutical composition are mannitol and sucrose at concentrations of about 47.36 mg/ml and about 13.69 mg/ml, respectively, and the amino acid is histidine hydrochloride in concentration of approximately 2.10 mg/ml, and the solubilizer is Tween 80 in an amount of approximately 0.02% (w/v). 17. The lyophilized pharmaceutical composition of claim 13, wherein the non-reducing sugars in the aqueous liquid pharmaceutical composition are mannitol and sucrose at concentrations of about 43.72 mg/ml and about 20.54 mg/ml, respectively, and the amino acid is histidine hydrochloride in concentration of approximately 2.10 mg/ml, and the solubilizer is Tween 80 in an amount of approximately 0.02% (w/v). 18. The use of a pharmaceutical composition according to any one of claims 1 to 17 in the manufacture of a medicament for the treatment of a disease caused by an abnormal expression of Her2, preferably cancer, more preferably Her2 positive cancer, and most preferably breast cancer, ovarian cancer, gastric cancer, urothelial cancer , gastroesophageal cancer, esophageal cancer, endometrial cancer, lung cancer, or bladder cancer. 19. A method for manufacturing a pharmaceutical composition of an antibody-drug conjugate, comprising: (1) making a composition according to any one of claims 1 to 17; And (2) evaluating the stability of the antibody-drug conjugate in the composition.